Substituted dibenzocyclooctene compositions

ABSTRACT

Certain new 5,6,7,12-tetrahydrodibenzo(a,d)-cyclooctene-12methylamines, as well as the N-alkyl and the N,N-dialkyl derivatives thereof, are prepared from the corresponding 5,6,7,12-tetrahydrodibenzo(a,d)cyclooctene-12-one by reduction with sodium borohydride to the corresponding 12-ol, conversion by treatment with hydrogen chloride to prepare the corresponding 12chloro compound, followed by reaction of the 12-chloro compound with silver cyanide to produce the corresponding 12-cyano compound. This 12-cyano compound is reduced with lithium aluminum hydride to produce the corresponding 12-methylamine which is then converted, if desired, to the corresponding N-alkyl, and/or N,Ndialkyl-5,6,7,12-tetrahydrodibenzo(a,d)cyclooctene-12methylamine. The cyclooctene-12-methylamine, as well as its Nalkyl and N,N-dialkyl derivatives, are active as antiarrhythmic agents.

' [75] Inventor:

United States Patent 1191 Christy SUBSTITUTED DIBENZOCYCLOOCTENE COMPOSITIONS Marcia E. Christy, Perkasie, Pa. [73] Assignee: Merck & Co., Inc., Rahway, NJ.

221 Filed: Nov. 7, 1972 [21] App]. No.: 304,581

Related U.S. Application Data [62] Division of Ser. No. 701,541, Jan. 30,- 1968,

abandoned.

[52] U.S. Cl 424/330; 424/330 [51] Int. Cl. A61K 31/135 OTHER PUBLICATIONS Winthrop et al., Jour. Med. Pharm. Chem., Vol. 6, pp. l30-132, (1963).

1 51 Sept. 23, 1975 Primary Examinere-Albert T. Meyers Assistant E.\'aminerDaren M. Stephens Atmrney, Agent, or F irm-Daniel T. S zura; Thomas E. Arther; Harry E. Westlake, Jr,

'[5 7] ABSTRACT Certain new 5 ,6,7, 1 2-tetrahydrodibenzo a,d ]-cyclooc tene-IZ-methylamines, as well as the N-alkyl and the N,N-dialkyl derivatives thereof, are prepared from the corresponding 5,6,7, 12-tetrahydrodibenzo[a,d]cyclooctene-lZ-one by reduction with sodium borohydride to the corresponding 12-01, conversion by treatment with hydrogen chloride to prepare the corresponding l2-ch1oro compound, followed by reaction of the l2-chloro compound with silver cyanide to produce the corresponding l2-cyano compound. This 12- cyano compound is reduced with lithium aluminum hydride to produce the corresponding l2-methylamine which is then converted, if desired, to the corresponding N-alkyl, and/or N,N-dialkyl-5 ,6,7,12- tetrahydrodibenzo[a,d lcyclooctenel Z-methylamine. The cyclooctene-IZ-methylamine, as well as its N- alkyl and N,N-dialkyl derivatives, are active as antiarrhythmic agents.

10 Claims, No Drawings ent.

1 SUBSTITUTED DIBENZOCYCLOOCTENE COMPOSITIONS ly-active amines, are represented structurally as dibenzocyclooctenes of the formula:

'as well as the corresponding N,N-dialkyl derivatives thereof.

wherein A is cyano substituent, an alkanoylaminomethyl substituent, an aminomethyl 'substituent, a monoalkyl-aminomethyl substituent or a dialkylaminomethyl substituent. Also included are derivatives of the compounds represented structurally hereinabove in which one or more of the hydrogens attached to the l, 2, 3, 4, 8, 9, 10 or 11 positions is replaced by halogen (fluorine, chlorine, bromine or iodine), alkyl (preferably having from l-6 carbon atoms), trifluoromethyl, alkoxy (preferably having from 1-5 carbon atoms, alkylsulfonyl (having from l-5 carbon atoms), alkylmercapto (having from l-5 carbon atoms), or dialkylsulfamoy] (having from l-4 carbon atoms).

An especially preferred group of compounds included within the scope of my invention, are represented by the formula:

'in which R is hydrogen or a loweralkyl substituent, said loweralkyl substituents having preferably from 1-5- carbon atoms.

Also included within the scope of the invention, are the non-toxicpharmaceutically acceptable-salts of the above compounds, thepreferred saltsbeing the nontoxic acidaddition salts such as the hydrochloride, the maleate, and the like, and pharmaceutical compositions of the above compounds, or. the salts in'combination with a non-toxic pharmaceutically acceptable dilu- Y pm] of the time.

2 Illustrative ofthe compounds included within the scope of the; invention are 5,6,7,12-

tetrahydrodibenzo[ a,d ]cyclooctenel Z-methylamine, the corresponding secondary amines as, for example,

the N-methyl, N -ethyL'N-propyl, N-isopropyl, N-butyl,

N-t-butyl, N-amyl and the N-hexyl derivatives thereof,

resumption of normal cardiac rhythm. As antiarrhythmic agents, these compounds may be administered orally or parentera lly. The formulations for administration may be prepared in conventional manner, employing conventional pharmaceutical carriers and excipients.

The non-toxic acid addition salts useful as components in the compositions provided by the present invention, are salts formed by the reaction of an equivalent amount of the amine compound of the above formula and an acid which is pharmacologically acceptablein the intended doses. Salts of the above compound which are useful are salts of the amine with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, acetic acid, propionic acid, lactic acid, gluconic acid, maleic acid, succinic acid, tartaric acid, and the like. Salts of these acids with the amine base are useful as the active component of the compositions in the method of this invention.

The daily doses are based on the total body weight of the test animal and vary between about 1.0 and 100.0 mg./kg. for mature animals. Thus, a unit dose based on 4-times-a-day administration is between 2.5 mg. and 250 mg. for a 10 kg. dog, and a total daily dose for a 10 kg. dog would vary between about 10 mg. and 1,000 mg. For larger animals, up to 100 kg. and above, proportional dosages are employed, based on the weight of the animal. Suitable dosage units provided for the administration of the compositions used in the method of the invention are tablets, capsules (which may be suitably formulated for either immediate or sustained release), syrups, elixirs, parenteral solutions, and the like. These dosage forms preferably contain per unit one or more multiples of the desired dosage unit in combination with the pharmaceutically acceptable diluent or carrier required for preparing the dosage unit.

Although the pharmaceutical compositions of my invention will ordinarily be administered within the ranges indicated, it is necessary for the skilled practitioner to determine the exact dosage, based on variables encountered in treating individual subjects. These variables include the age, sex, general health, and'various other factors and, in part, will all affect the determination of the exact amount of active ingredient to be administered, as well as the route of administration.

The compounds represented by the above structural formula may be prepared as illustrated below:

I reduction Intermediate O 7 ll H v CH NHCR 60 wherein X and X are hydrogen, halogen, alkyl, trifluopropriately f stibstituted l2-chloro-5,6,7,l2-

tetrahydrodibenzo"a,d]cyclooctene with a metal cyanide such as cuprous cyanide or silver cyanide in a suitable anhydrous non-hydroxylic solvent such as benzene, toluene ,'chloroform or acetonitrile to produce the corresponding 1 Z-cyano tetrahydrodibenzo[ a,d]cyclooctene. The temprature'at which the reaction is carried out is not critical, but it is preferred to employ elevated temperatures in the range of about 50lO0C. The desired-product is readily recovered employing conventional techniques to remove the metal salts which precipitate from the reaction mixture, followed by filtration and evaporation of the solvent and crystallization of the product from solvents. i

The thus-obtained l2-cyano-substitutedj dibenzocyclooctene is then reduced to produce the corresponding l2-methylamine. The reduction is readily effected by contacting the l2-cyano compound with lithium aluminum hydride in the presence of a suitable inert organic solvent such as tetrahydrofuran, ether, or other solvent conventionally employed with lithium aluminum hydride. Preferably, this reduction is carried out in the presence of aluminum chloride and an ether compatible with aluminum chloride asa solvent. The temperature at which the reduction is carried out is not critical, but it is preferred to employ elevated temperatures up to about 50C. The resulting aminomethyl derivative is readily recovered employing conventional techniques. The l2-formamidomethyl derivative (II) is prepared by formylation of the aminomethyl compound (l) employing conventional conditions and reagents, such as formic acid or esters thereof, for this purpose. The resulting formamidomethyl derivative can be recovered in the conventional manner. The dimethylaminomethyl derivative (III) is readily prepared by the treatment of the primary amine compound (I) with formaldehyde and formic acid in accordance with the known Eschweiler-Clarke modification of the Leuckart Reaction. Recovery of the dimethylaminomethyl derivative is accomplished in conventional manner. The methylaminomethyl compounds (IV) may be prepared by either reduction of the formamidomethyl derivative (II) or by mono-dealkylation of the dimethylaminom ethyl derivative (III). Reduction of the formamidomethylderivative is effected under the firstdescribed conditions set forth above for carrying out the reduction of the l2-cyano derivative. Similarly, dealkylation of (III) can be effected inknown manner such as by treatment with cyanogen bromide followed by hydrolysis of the intermediate cyanamide or by treatment with a haloformate followed by hydrolysis of the urethane intermediate. In each instance, the desired compound can be recovered employing conventional techniques.

The N-loweralkylamines and the N,N- diloweralkylamines corresponding to compounds IV and Ill, respectively, are likewise prepared from the corresponding primary amine l by analogous reactions. Thus, the primary amine l is treated with a lower aliphatic acid halide or anhydride of from 2 -5 carbon atoms. e.g., acetyl chloride, acetic anhydride, propionyl chloride, butyryl chloride or valeryl chloride to produce the N -alkanoyl amide corresponding to II as, for example, the N-acetyl, N-propionyl, N-butyryl or N- valeryl amine. The thus-obtained amide is reducedto the corresponding l2-N-loweralkylaminomethyl compound by reduction in the manner described for the corresponding l2-cyano compound, i.e., reduction with lithium aluminum hydride. The secondary amine compounds produced in this manner are the 12- (loweralkyl) derivatives of 5,6,7,l2tetrahydrodibenzo- [a,dlcyclooctene-l2-methylamine as, for example, the l2-(ethyl), l2-(propyl), l2-(butyl) and the l2-(amyl) derivatives. The corresponding tertiary amines, the N,N-diloweralkyl derivatives, are prepared from the secondary amines by repeating the process employed in the preparation of the secondary amines. Thus, the amides-of the secondary amines are prepared and reduced with lithium aluminum hydride to produce the correspondingtertiary amines as, for example, the corre-' sponding hydroxy-5,6,7,l2tetrahydrobenzo[a,d]cyclooctene, as

described by S. O. Winthrop, M. A. Davis, F. Herr, J. Stewart and R. Gaudry, J. Med. Chem. 6, -132 (1963), followed by treatment with hydrogen chloride to produce the corresponding 12-chloro-5,6,7,l 2- tetrahydrodibenz0[a,d]cyclooctene. The thus-obtained l2-chloro compound is then treated with silver cyanide in a suitable anhydrous non-hydroxylic solvent and at a suitable temperature, preferably in the range of 50- l50C.

The following examples are illustrative but not limitative of the invention.

EXAMPLE 1 l2-Cyano-5 ,6,7, l 2-tetrahydrodibenzo[a,d cyclooctene 5 ,6,7,l2-Tetrahydrodibenzo[a,d]cyclootene-12-01, 5.95 g. (0.0266 mole), is dissolved in 210 ml. of dry benzene and the ice-cold solution saturated with hydro gen chloride. The mixture is allowed to stand for 3 /2 hours, with additional passageof hydrogen chloride through the solution for 5 minutes at the end of the first hour The excess hydrogen chloride and the bulk of the solvent are evaporated under reduced pressure at 3035C., leaving l2-chloro-5,6,7,l2- tetrahydrodibenzo[a,d]cyclooctene as the residual oil.

The crude chloride is dissolved in ml. of dry acetonitrile and stirred at reflux with 5.35 g. (0.04 mole) of silver cyanide. After about 18 hours, 50 ml. of dry benzene is added and refluxing is continued for another 24 hours. Silver salts are removed by filtration and washed with boiling benzene. Evaporation of the solvents under reduced pressure and crystallization of the residue from cyclohexane yields product, m.p. l88l92C. A purified sample melts at l93l94C. after repeated crystallizations from cyclohexane.

Anal. Calcd. for C l-l Nz' C, 87.50; H, 6.48.

Found: C, 86.81; H, 5.68.

EXAMPLE 2 5 ,6,7, 1 2-Tetrahydrodibenzo[a,d cyclooctenel 2- methylamine Lithium aluminum hydride, 0.304 g. (0.008 mole) is weighed under nitrogen, transferred to a dry, nitrogenflushed reaction flask, and suspended in 10 ml. of absolute ether. A solution of 1.05 g. (0.008 mole) of aluminum chloride in 20 ml. of absolute ether is added dropwise and the mixture is stirred for 5 minutes at room temperature. A solution of 0.90 g. (0.00386 mole) of l2-cyano-5 ,6,7, l 2-tetrahydrodibenzo[a,d]cyclooctene in 100 ml. of absolute ether then is added dropwise and the mixture is stirred at room temperature for about 17 hours under a slow stream of nitrogen. The adduct is hydrolyzed by the dropwise addition of 8 ml. of water. The ethereal solution is decanted and the gelatinous precipitate washed with ether. The precipitate is shaken with 20 ml. of N aqueous sodium hydroxide and 50 ml. of water, and the mixture extracted with three portions of benzene. Evaporation of the combined extracts under reduced pressure leaves the product as the oily base.

The base is converted to the hydrogen oxalate salt by treating an ethanolic solution of the base with a slight excess of oxalic acid in ethanol. The hydrogen oxalate separates in white crystals, m. p. 2l62l8C. dec. An analytical sample melts at 219220C. dec., after repeated crystallizations from methanol.

Anal. Calcd. for C H N. C H O C, 69.70; H, 6.47; N, 4.28.

Found: C, 69,36; H, 6.25; N, 4.25.

EXAMPLE 3 N-( 5 ,6,7,l2-Tetrahydrodibenzo[a,d]cyclooctene-12- methyl )-formamide 5,6,7,l 2-Tetrahydrodibenzo[a,d]cyclooctene-12- methylamine, 0.245 g. (0.001 mole), is heated to refluxing in ml. of ethyl formate for 5%. hours. Evaporation of the solution under reduced pressure leaves the product as the crystalline residue, m.p. l95l96C. A purified sample melts at 196-l97.5C. after recrystallization from benzene hexane.

Anal. Calcd. for C H NO: C, 81.47; H, 7.22; N, 5.28.

Found: C, 81.32; H, 6.97; N, 5.24.

EXAMPLE 4 N-Methyl-S ,6,7 ,1Z-tetrahydrodibenzo[a,d]cyclooctene-l 2-methylamine Lithium aluminum hydride, 0.33 g. (0.0087 mole) is weighed under nitrogen, transferred to a dry, nitrogenflushed reaction flask, and suspended in ml. of absolute ether. A solution of 1.1 g. (0.00415 mole) of N- (5 ,6,7,12-tetrahydrodibenzo[a,d]cyclooctene-12- methyl)-formamide in 950 ml. of absolute ether is added rapidly dropwise and the mixture is stirred at reflux for about 18 hours. After cooling in an ice-bath, the complex is hydrolyzed by the successive dropwise addition of 0.5 ml. of water, 0.5 ml. of 15% aqueous sodium hydroxide, and 1.0 ml. of watenThe precipitate is removed by filtration and the ethereal filtrate evaporated under reduced pressure, leaving the product as the residual oily base.

The hydrochloride is prepared from the base by treating an ethanolic solution with a slight excess of ethanolic hydrogen chloride. Dilution with absolute ether precipitates the crystalline salt. A purified sample melts at 269C. dec., after recrystallizations from ethanol ether.

Anal. Calcd. for C H N. HCl: C, 75.11; H, 7.71;

Found: C, 74.86; H, 7.83.

EXAMPLE 5 N,N-Dimethyl-5,6,7, l2- tetrahydrodibenzo[a,d]cyclooctene-12-methylamine 5,6,7,l2-Tetrahydrodibenzo[a,d]cyclooctene-12- methylamine, 1.2 g (0.005 mole), and 0.9 g. (0.011 mole) of 36-38% aqueous formaldehyde in 3 ml. of 88% formic acid are heated on the steam-bath for ing products are also prepared as set forth in the preceding description.

Flow Sheet Example Formula X X 6 Intermediate H Chloro 7 H Bromo 8 H Methyl 9 H Tert-butyl l0 H Methoxy l l H Ethoxy l 3 H Methylsulfonyl l4 H Methylmercapto 15 H Dimethylsulfamoyl l6 Bromo Chloro 17 Bromo Dimethylsulfamoyl l8 Methyl Methyl 19 Intermediate C hloro Methyl 20 Chloro Dimethylsulfamoyl 21 Chloro Chloro 22 l H Chloro 23 H Bromo 24 H Methyl 25 H Tert-butyl 26 H Mcthoxy 27 H Ethoxy 28 H Trifluoromethyl 29 H Methylsulfonyl 30 H Methylmercapto 3 1 H Dimethylsulfamoyl 32 Bromo Chloro 33 Bromo Dimethylsulfamoyl 34 Methyl Methyl 35 Chloro Methyl 36 Chloro Dimethylsulfamoyl 37 C hloro Chloro 38 Ill Derivatives of each of compounds of Formula 1 above in which R 2 and R are each methyl, ethyl, propyl, butyl or amyl.

39 1V Derivatives of each of the compounds of Formula 1 above in which R, is methyl, ethyl, propyl, butyl or amyl.

EXAMPLE 40 Prevention or Modification of Ventricular Arrhythmia Beagle dogs of either sex, and weighing from 6 to 10 kg. are anesthetized by the administration of vinbarbital employing a dose of 50 mg./kg. of body weight, and the mean arterial pressure and the electrocardiogram (Lead II) are recorded. The animals are articfically respired and the thorax opened at the fourth or fifth interspace. The pericardium is opened and a portion of the anterior descending coronary artery just distal to the origin is freed from the surrounding tissue. Mecamylamine is administered to slow the heart rate and 10 minutes later the compound to be tested for anitarrythmic effect is administered intravenously. Ten minutes after administration of the test compound 0.0035

ml./kg. of tetrafluorohexachlorobutane (TFHCB), a

sclerosing agent which produces myocardial infarction and arrhythmia in dogs (Ascanio et a1., .1. Am. Physio].

209: 1081-1088 (1965)), is injected into the coronary artery. Followinginjectio'n of theisc'lerosirig agent, the electrocardiogram is recorded at 2-minute intefvals for one hour, andthe average number'of 'electrica l "(.ECG)

complexes per minute and the percent normal complexes calculated.

In control animals, the dose of sclerosing agent used produces a ventricular arrhythmia in 100% of the 'ani.

mals tested, and death in 33% as a result of ventricular fibrillation. In control animals, on the average, fewer than 20% of all recorded ECG. complexes are normal.

The test compound, 5,6,7,l2-tetrahydrodibenzo[ a,- d]cyclooctene-lZ-methylamine, was demonstrated to have antiarrhythmic activity and in these experiments at 5.0 mg./kg. on the average 70% of all ECG com; plexes were normal and none of the animals succumbed to ventricular fibrillation.

EXAMPLE 4 Tablets,

Tablets for oral administration are prepared by mixing the active ingredient with appropriate amounts of excipients and binding agents, formed into tablets by a conventional tableting machine and coated so that each tablet will have the following composition.

Per Tablet N-methyl-S ,6,7, l 2-tetrahydrodibenzo [a,d cyclooctene-IZ- methylamine hydrochloride l mg. Cellulose filter aid 1 l mg. Lactose 9 mg. Calcium Phosphate Dibasic 143 mg. Guar Gum 6.! mg. Corn Starch 4 mg. Magnesium Stearate 0.9 mg. Opaque yellow film coating 3 mg.

EXAMPLE 42 Capsules Capsules for oral administration are prepared by dispersing the active ingredient in lactose and magnesium stearate and encapsulating the mixture in standard soft gelatin capsules so that each capsule will have the following composition.

Per Capsule N-methyl-5.6,7,IZ-tetrahydrodibenzo [ad 1 cyclooctene-lZ- methylamine hydrochloride mg. Lactose 430 mg. Magnesium Stearate 5 mg.

EXAMPLE 43 Parenteral Solution A solution suitable for administration for injection is prepared by mixing the active ingredients, Dextrose, methylparaben, propylparaben and distilled water, so that each one will have the following composition, and sterilized.

Pcr ml.

N-methyl-5,6.7. l 2 tetrahydrodibenzo [a.d cyclooctenc-IZ- methylamine-hydrochloride 5 mg.

' Dextrose 44 mg;

Methylparaben 'l'.5 mg. Propylparaben 0.2 mg. .Water for Injection q.s.

The preceding three examples, Examples 41 42' and I 43, are repeated, and compositions for the treatment or prevention of arrhythmia are prepared by substituting any of the compounds specificallyillustrated above in place of the 5,6,7,l2-tetrahydrodibenzo[a,d]cyclooctene asoneof the active compounds usefulin my invention.

I claim:

l. Apharmaceutical composition comprising an antiarrhythmia effective amount of a.;compound of the formula in which R and R are hydrogen or lower alkyl substituents having from l-5 carbon atoms or a derivative of the compound of the above structural formula wherein one or more of the hydrogens attached to the l, 2, 3, 4, 8, 9, 10 or 1 1 positions is replaced by halogen, alkyl, trifluoromethyl, alkylsulfonyl, alkylmercapto or dialkylsulfamoyl.

3. Pharmaceutical composition comprising an antiarrthythmia effective amount of a compound having the formula:

10. Pharmaceutical composition comprising an antiarrthyrnia effectiveamount of a non-toxic, pharmaceutically acceptable, acid addition salt of a compound having the formula A. r V

. H CH in which R and R are hydrogen or lower alkyl substitutents having from 1-5 carbon atoms or a derivative of the compound of the above structural formula wherein one or more of the hydrogens attached to the l, 2, 3, 4, 8, 9, 10 or 1 1 positions is replaced by halogen, alkyl, trifluoromethyl, alkylsulfonyl, alkylmercapto or dialkylsulfamoyl in combination with a nontoxic pharmaceutically acceptable diluent.

' g if 

1. A PHARMACEUTICAL COMPOSITION COMPRISING AN ANTIARRHYTHMIA EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA
 2. A METHOD FOR TREATING OR PREVENTING ARRHYTHMIA IN ANIMALS WHICH COMPRISES ADMINISTERING TO AN AFFLICTED ANIMAL AN EFFECTIVE AND NON-TOXIC DOSE OF AN ACTIVE COMPOUND HAVING THE FORMULA 12-(R2-N(-R3)-CH2-)-5,6,7,12-TETRAHYDRODIBENZO(A,D)CYCLOOCTENE IN WHICH R2 AND R3 HYDROGEN OR LOWER ALKYL SUBSTITUENTS HAVING FROM 1-5 CARBON ATOMS OR A DERIVATIVE OF THE COMPOUND OF THE ABOVE STRUCTURAL FORMULA WHEREIN ONE OR MORE OF THE HYDROGENS ATTACHED TO THE 1,2,3,4,8,9, 10 OR 11 POSITIONS IS REPLACED BY HALOGEN ALKYL TRIFLUOROMETHYL ALKYLSULFONYL ALKYLERCAPTO OR DIALKYLSULFAMOYL.
 3. Pharmaceutical composition comprising an antiarrthythmia effective amount of a compound having the formula:
 4. Composition of claim 1 wherein R2 and R3 are hydrogen.
 5. Composition of claim 3 wherein R2 and R3 are hydrogen.
 6. Composition of claim 3 wherein R3 is hydrogen.
 7. Composition of claim 6 wherein R2 is methyl.
 8. Composition of claim 6 wherein R2 and R3 are lower alkyl.
 9. Composition of claim 8 wherein R2 and R3 are methyl.
 10. Pharmaceutical composition comprising an antiarrthymia effective amount of a non-toxic, pharmaceutically acceptable, acid addition salt of a compound having the formula 